The rough endoplasmic reticulum (ER) serves as the entry point into the secretory pathway for newly-synthesized hormones and enzymes. Accordingly, the rough ER mediates highly-efficient translocation of nascent polypeptides from the cytoplasm into its lumen. In tissues where high levels of secretion are demanded, the rough ER is so abundant that it dominates the sub-cellular landscape. Proliferation of ER is induced in cells and tissues in response to intoxication, or when cells are stimulated to secrete large quantities of proteins. It is the purpose of the research described here to focus on the mechanism of how stimulated proliferation of the rough ER is accomplished. Bound ribosomes represent the distinguishing feature of rough ER. A mammalian rough ER-specific protein that was previously isolated and characterized as having a high-affinity for ribosomes and a remarkable primary structure induces rough membrane proliferation upon its expression in yeast and mammalian cells. The hypothesis that there is a specific signaling pathway leading to ER membrane proliferation can now be tested in model systems using a balance of biochemical, cell biological and genetic approaches. Factors will be identified and characterized that enable cells, from yeast to mammals, to upregulate their mass of rough ER. Preliminary results indicate that in yeast, it is possible to upregulate the entire secretory pathway, thus paving the way for an investigation of the regulation of this complex and important intracellular pathway in a genetically-tractable organism.